NO324946B1 - 3- (heteroarylacetamido) -2-oxo-azetidine-1-sulfonic acid derivatives as antibacterial agents, as well as their preparation and use and pharmaceutical composition - Google Patents
3- (heteroarylacetamido) -2-oxo-azetidine-1-sulfonic acid derivatives as antibacterial agents, as well as their preparation and use and pharmaceutical composition Download PDFInfo
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- NO324946B1 NO324946B1 NO20031162A NO20031162A NO324946B1 NO 324946 B1 NO324946 B1 NO 324946B1 NO 20031162 A NO20031162 A NO 20031162A NO 20031162 A NO20031162 A NO 20031162A NO 324946 B1 NO324946 B1 NO 324946B1
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- Prior art keywords
- compound
- formula
- hydrogen
- preparation
- sulfonic acid
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- 239000003242 anti bacterial agent Substances 0.000 title description 10
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
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- 230000003287 optical effect Effects 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 53
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 159000000000 sodium salts Chemical class 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- NSRVGDULUQOEBX-UHFFFAOYSA-N 3-amino-2-oxoazetidine-1-sulfonic acid Chemical compound NC1CN(S(O)(=O)=O)C1=O NSRVGDULUQOEBX-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 150000001768 cations Chemical class 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
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- 239000000829 suppository Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 241000589516 Pseudomonas Species 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
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- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 3
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- 229920001249 ethyl cellulose Polymers 0.000 description 1
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- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
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- 239000007951 isotonicity adjuster Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
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- 229920000609 methyl cellulose Polymers 0.000 description 1
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- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 description 1
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- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 description 1
- CIAOJLKEFVPKRX-UHFFFAOYSA-N octadecapotassium;fluoro(dioxido)borane Chemical compound [K+].[K+].[K+].[K+].[K+].[K+].[K+].[K+].[K+].[K+].[K+].[K+].[K+].[K+].[K+].[K+].[K+].[K+].[O-]B([O-])F.[O-]B([O-])F.[O-]B([O-])F.[O-]B([O-])F.[O-]B([O-])F.[O-]B([O-])F.[O-]B([O-])F.[O-]B([O-])F.[O-]B([O-])F CIAOJLKEFVPKRX-UHFFFAOYSA-N 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920001289 polyvinyl ether Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- GGOZGYRTNQBSSA-UHFFFAOYSA-N pyridine-2,3-diol Chemical compound OC1=CC=CN=C1O GGOZGYRTNQBSSA-UHFFFAOYSA-N 0.000 description 1
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- 230000009257 reactivity Effects 0.000 description 1
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- 235000013874 shellac Nutrition 0.000 description 1
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- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Foreliggende oppfinnelse vedrører 3-(heteroarylacetamido)-2-okso-azetidin-1-sulfonsyre-derivater som antibakterielle midler, samt fremstilling og anvendelse derav og farmasøytisk preparat. Forbindelsene kan anvendes for behandling av infeksjoner forårsaket av gram-negative patogene bakterier. The present invention relates to 3-(heteroarylacetamido)-2-oxo-azetidine-1-sulfonic acid derivatives as antibacterial agents, as well as the manufacture and use thereof and pharmaceutical preparations. The compounds can be used for the treatment of infections caused by gram-negative pathogenic bacteria.
Bakerier er meget tilpasningsdyktige mikroorganismer som innehar evnen til å tilpasse seg og overleve under forskjellige betingelser. Leger i sykehus og klinikere rundt om i verden er i ferd med å tape kampen mot bekjempelse av nye medikamentresistente bakerielle infeksjoner som inkluderer de som blir forårsaket av Staphylococci, Streptococci, Enterococci og Pseudomonas. Bacteria are highly adaptable microorganisms that have the ability to adapt and survive under different conditions. Hospital doctors and clinicians around the world are losing the battle to combat new drug-resistant bacterial infections that include those caused by Staphylococci, Streptococci, Enterococci and Pseudomonas.
Bakteriell motstand overfor gjeldende antibiotika har vært sterkt økende grunnet endring av mål, en forandring i permeabilitetsmønsteret eller grunnet utløp av aktivt ingrediens eller ved deaktivering av antibiotika før de når det aktive setet. Bacterial resistance to current antibiotics has been greatly increasing due to a change in target, a change in the permeability pattern or due to leakage of active ingredient or by deactivating antibiotics before they reach the active site.
p-laktam antibiotika (penicilliner, sefalosporiner, monobaktamer og karbapenemer) er den oftest anvendte gruppen av antibiotika for behandling av mange infeksiøse sykdommer på grunn av at bevist klinisk effektivitet og deres gode profil når det gjelder trygghet. Bakteriell motstand overfor gram-positive patogener mot p-laktam antibiotika skyldes hovedsakelig endring av penicillinbindende proteiner (PBP), utløp av aktivt ingrediens og deaktivering av aktivt ingrediens. Mens bakteriell motstand overfor gram-negative patogener mot (3-laktam antibiotika i tillegg til gram-positive patogener også skyldes forandringer i ytre membran permeabilitets-mønstere. p-lactam antibiotics (penicillins, cephalosporins, monobactams and carbapenems) are the most commonly used group of antibiotics for the treatment of many infectious diseases due to their proven clinical effectiveness and their good safety profile. Bacterial resistance of gram-positive pathogens to β-lactam antibiotics is mainly due to alteration of penicillin-binding proteins (PBP), leakage of active ingredient and deactivation of active ingredient. While bacterial resistance to gram-negative pathogens against (3-lactam antibiotics in addition to gram-positive pathogens is also due to changes in outer membrane permeability patterns.
For å løse forandringer i permeabiliteten til den ytre membranen, er i de senere årene et antall p-laktam forbindelser (sefem og monobaktam) inneholdende jernkelaterende katekolin og dihydroksypyridongrupper blitt beskrevet (29Th ICAAC, Houston Texas, 18. september 1989, utdrag nr. 355, 356; 30 Th ICAAC, Atlanta, Georgia, 22. oktober 1990, utdrag nr. 458; Antimicrobial Agents and chemotherapy 1991, 35, 104-110). Den potente aktiviteten til disse forbindelsene skyldes deres anvendelse av TonB-avhengige jerntransportsystemer for transport over den bakterielle ytre membranen (Antimicrobial Agents and chemotherapy 1995, 39, 613-619). To address changes in the permeability of the outer membrane, in recent years a number of β-lactam compounds (cefem and monobactam) containing iron-chelating catecholin and dihydroxypyridone groups have been described (29Th ICAAC, Houston Texas, September 18, 1989, abstract no. 355 , 356; 30 Th ICAAC, Atlanta, Georgia, 22 October 1990, Abstract No. 458; Antimicrobial Agents and chemotherapy 1991, 35, 104-110). The potent activity of these compounds is due to their use of TonB-dependent iron transport systems for transport across the bacterial outer membrane (Antimicrobial Agents and chemotherapy 1995, 39, 613-619).
Monobaktamer er en klasse antibakterielle midler og er blitt anvendt for å behandle infeksjoner forårsaket av gram-negative mikroorganismer. For tiden er Aztreonam og Carumonam i klinisk bruk. Quinoksalin direkte koplet til en oksimsidekjede av monobactamkjernen er under utvikling (Curr. Opin. Anti-infect. Drugs 1999, 1(1), 96-100; Antimicrobial Agents and Chemotherapy 1997, 41, 1010-1016). Videre blir dihydroksypyridin gjennom en metylenspacer koplet til en oksimsidekjede i antiorientering rapportert som p-laktamaseinhibitor (USP-588998 Monobactams are a class of antibacterial agents and have been used to treat infections caused by gram-negative microorganisms. Currently, Aztreonam and Carumonam are in clinical use. Quinoxaline directly linked to an oxime side chain of the monobactam core is under development (Curr. Opin. Anti-infect. Drugs 1999, 1(1), 96-100; Antimicrobial Agents and Chemotherapy 1997, 41, 1010-1016). Furthermore, dihydroxypyridine through a methylene spacer coupled to an oxime side chain in anti-orientation is reported as a β-lactamase inhibitor (USP-588998
(1999)). (1999)).
Foreliggende oppfinnelse beskriver en klasse av forbindelser hvor en dihydroksypyridongruppe er direkte eller gjennom en egnet spacer koplet til en oksimsidekjede i en monobaktamkjerne og anvendelse derav for behandling av gram-negative infeksjoner, spesielt de som blir forårsaket av Pseudomonas, Pseudomonas aeruginosa er fortsatt et meget opportunistisk patogen med evne til å forårsake en rekke infeksjoner i immunkomprimiterte pasienter. Disse infeksjonene er ofte assosiert med betydelig morbiditet og er vanskelig å behandle. The present invention describes a class of compounds where a dihydroxypyridone group is directly or through a suitable spacer linked to an oxime side chain in a monobactam core and its use for the treatment of gram-negative infections, especially those caused by Pseudomonas, Pseudomonas aeruginosa is still a very opportunistic pathogen capable of causing a variety of infections in immunocompromised patients. These infections are often associated with significant morbidity and are difficult to treat.
Oppsummering av oppfinnelsen Summary of the invention
Det er en hensikt ifølge foreliggende oppfinnelse å tilveiebringe nye forbindelser med formel I som har antibakteriell aktivitet mot gram-negataive patogene bakterier, spesielt Pseudomonas-stammer. It is an aim according to the present invention to provide new compounds of formula I which have antibacterial activity against gram-negative pathogenic bacteria, especially Pseudomonas strains.
Foreliggende oppfinnelse vedrører følgelig forbindelse kjennetegnet ved at den har formel I The present invention therefore relates to a compound characterized by having formula I
hvor where
M er et hydrogenatom eller et farmasøytisk akseptabelt saltdannende kation; XerCH; M is a hydrogen atom or a pharmaceutically acceptable salt-forming cation; XerCH;
R er C1-C3 alkyl som er usubstituert eller substituert med minst et halogenatom eller OR5 hvor R5 er hydrogen eller CONH2; R is C1-C3 alkyl which is unsubstituted or substituted by at least one halogen atom or OR5 where R5 is hydrogen or CONH2;
Ri er OH og R2 er hydrogen; eller R 1 is OH and R 2 is hydrogen; or
Ri og R2 er sammen -CH=C(OH)-C(OH)=CH- som sammen med karbonatomene som de er bundet til, danner en seksleddet cyklisk ring; og R1 and R2 together are -CH=C(OH)-C(OH)=CH- which, together with the carbon atoms to which they are attached, form a six-membered cyclic ring; and
R3 og R4 er uavhengig hydrogen; eller R 3 and R 4 are independently hydrogen; or
R3 og R4 er sammen med karbonatomet de er bundet til C3-C6 cykloalkyl. R 3 and R 4 together with the carbon atom they are attached to are C 3 -C 6 cycloalkyl.
Det er videre en hensikt ifølge oppfinnelsen å tilveiebringe fremgangsmåte for fremstilling av et zwitterion av forbindelsen med formel I, kjennetegnet ved at M er hydrogen, og hvor nevnte forbindelse reageres med et basisk nitrogenatom til stede i molekylet med formel I. It is a further purpose according to the invention to provide a method for producing a zwitterion of the compound of formula I, characterized in that M is hydrogen, and where said compound is reacted with a basic nitrogen atom present in the molecule of formula I.
Det er i tillegg en hensikt ifølge oppfinnelsen å tilveiebringe en fremgangsmåte for fremstilling av en forbindelse ifølge krav 1 eller krav 7, kjennetegnet ved at den omfatter (a) omsetning av en 3-aminoazetidin-2-onsulfonsyre med formel (II) med en heteroarylkarboksylsyre med formel (III) og (b) fjerning av beskyttelsesgruppen. It is additionally a purpose according to the invention to provide a method for producing a compound according to claim 1 or claim 7, characterized in that it comprises (a) reaction of a 3-aminoazetidin-2-one sulfonic acid of formula (II) with a heteroarylcarboxylic acid of formula (III) and (b) removal of the protecting group.
Foreliggende oppfinnelse vedrører videre farmasøytisk preparat kjennetegnet ved at det omfatter en forbindelse ifølge et hvilket som helst av kravene 1 til 5 og 7 til 10 og en farmasøytisk akseptabel bærer. The present invention further relates to a pharmaceutical preparation characterized in that it comprises a compound according to any one of claims 1 to 5 and 7 to 10 and a pharmaceutically acceptable carrier.
Det er videre beskrevet anvendelse av en forbindelse ifølge et hvilket som helst av kravene 1 til 5 og 7 til 10, for fremstilling av et medikament for behandling av en bakteriell infeksjon. It is further described the use of a compound according to any one of claims 1 to 5 and 7 to 10, for the production of a medicament for the treatment of a bacterial infection.
Detaljert beskrivelse av oppfinnelsen Detailed description of the invention
I henhold til foreliggende oppfinnelse er det tilveiebrakt nye forbindelser med formel I According to the present invention, new compounds of formula I have been provided
Som anvendt heri, betyr betegnelsen "C1-C3 alkyl" en lineær eller forgrenet alkyl med 1-3 karbonatomer valgt fra metyl, etyl, propyl eller isopropyl. As used herein, the term "C1-C3 alkyl" means a linear or branched alkyl having 1-3 carbon atoms selected from methyl, ethyl, propyl or isopropyl.
Som anvendt heri, angir betegnelsen "C3-C6 cykloalkyl" en mettet alicyklisk gruppe med 3-6 karbonatomer valgt fra cyklopropyl, cyklobutyl, cyklopentyl og cykloheksyl. As used herein, the term "C3-C6 cycloalkyl" denotes a saturated alicyclic group of 3-6 carbon atoms selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Som anvendt heri, betyr betegnelsen "halogenatom" fluor, klor eller brom. As used herein, the term "halogen atom" means fluorine, chlorine or bromine.
Som anvendt heri, betyr betegnelsen "substituert" når det gjelder en gruppe, substituert med 1, 2 eller 3 substituenter valgt fra OH, NH2, dimetylamino, et halogenatom, OCH3, COOH, CONH2, N02 eller CN. As used herein, the term "substituted" means a group substituted with 1, 2 or 3 substituents selected from OH, NH 2 , dimethylamino, a halogen atom, OCH 3 , COOH, CONH 2 , NO 2 or CN.
Som anvendt heri, betyr betegnelsen "rasemat" blanding av diasteroisomerer med null optisk rotasjon i molekylet med formel I. As used herein, the term "racemate" means the mixture of diastereoisomers with zero optical rotation in the molecule of formula I.
Som anvendt heri, betyr betegnelsen "optiske isomerer" rene enkelt R og S diastereoisomerer som asymetriske karbonatomer til stede i molekylet med formel I. As used herein, the term "optical isomers" means pure single R and S diastereoisomers as asymmetric carbon atoms present in the molecule of formula I.
Som anvendt heri, angir betegnelsen "farmasøytisk alseptabelt saltdannende kation" alkalimetaller (f. eks. natrium, kaliuim), jordalkaliske metaller (f. eks. kalsium, magnesium), organiske baser (f. eks. trietylamin, etanoloamin, n-metylmorfolin) eller basiske aminosyrer (f. eks. lysin, arginin, ornitin eller histidin). Videre når M er hydrogen i formel I, kan den danne zwitterioner (indre salt) ved å reagere med et basisk nitrogenatom til stede i molekylet med formel I. As used herein, the term "pharmaceutically acceptable salt forming cation" refers to alkali metals (eg, sodium, potassium), alkaline earth metals (eg, calcium, magnesium), organic bases (eg, triethylamine, ethanolamine, n-methylmorpholine) or basic amino acids (eg, lysine, arginine, ornithine, or histidine). Furthermore, when M is hydrogen in formula I, it can form zwitterions (inner salt) by reacting with a basic nitrogen atom present in the molecule of formula I.
Som anvendt heri, betyr betegnelsen "rasemat" blanding av diastereisomerer som har null optisk rotasjon i molekylet med formel I. As used herein, the term "racemate" means the mixture of diastereoisomers having zero optical rotation in the molecule of formula I.
Som anvendt heri, betyr betegnelsen "optiske isomerer" rene enkelt R og S diastereoisomerer ved asymetriske karbonatomer til stede i molekylet med formel I. As used herein, the term "optical isomers" means pure single R and S diastereoisomers at asymmetric carbon atoms present in the molecule of formula I.
Som anvendt heri, betyr betegnelsen "farmasøytisk akseptabelt saltdannende kation" alkalimetaller (f. eks. natrium, kalium). Videre når M er hydrogen i formel I, kan den danne zwitterion (indre salt) ved å reagere med et basisk nitrogenatom til stede i molekylet med formel I. As used herein, the term "pharmaceutically acceptable salt-forming cation" means alkali metals (eg, sodium, potassium). Furthermore, when M is hydrogen in formula I, it can form zwitterion (inner salt) by reacting with a basic nitrogen atom present in the molecule of formula I.
Forbindelser ifølge denne oppfinnelsen kan bli anvendt for å behandle bakterielle infeksjoner forårsaket av gram-negative bakterier, inkludert men ikke begrenset til Pseudomonas E. eloaecae, C. freundii, M. Morganii, K. paeumoniae og E. Coli, alene eller i kombinasjon med andre medikamenter i pattedyr inkludert mennesker. Forbindelsene kan bli administrert i farmasøytiske doseringsformer som inkluderer parenteral preparering så som injeksjoner, suppositorier, aerosoler og liknende, og orale preparater så som tabletter, belagte tabletter, pulvere, granuler, kapsler, væsker og liknende. Ovennevnte preparater blir formulert på måter som er velkjente innenfor fagområdet. Compounds of this invention can be used to treat bacterial infections caused by Gram-negative bacteria, including but not limited to Pseudomonas E. eloaecae, C. freundii, M. Morganii, K. paeumoniae and E. Coli, alone or in combination with other drugs in mammals including humans. The compounds may be administered in pharmaceutical dosage forms which include parenteral preparations such as injections, suppositories, aerosols and the like, and oral preparations such as tablets, coated tablets, powders, granules, capsules, liquids and the like. The above preparations are formulated in ways that are well known in the art.
For formulering av faste preparater for oral administrering blir en eksipient, og om ønskelig, et bindemiddel, et oppløsningsmiddel, et smøremiddel, et farvemiddel, korrigeringsmiddel, smaksmiddel osv. tilsatt til forbindelsen ifølge oppfinnelsen, og deretter blir tabletter, belagte tabletter, granuler, pulvere, kapsler eller liknende fremstilt på konvensjonell måte. For the formulation of solid preparations for oral administration, an excipient and, if desired, a binder, a solvent, a lubricant, a coloring agent, a correcting agent, a flavoring agent, etc. are added to the compound according to the invention, and then tablets, coated tablets, granules, powders , capsules or the like produced in a conventional manner.
For formulering av injeksjoner, blir et pH justerende middel, en buffer, en stabilisator, isotinisk middel, lokalbedøvelsesmiddel eller liknende tilsatt til det aktive ingredienset ifølge oppfinnelsen, og injeksjoner for subkutan, intramuskulær eller intravenøs administreirng kan bli dannet på konvensjonell måte. For the formulation of injections, a pH adjusting agent, a buffer, a stabilizer, isotonic agent, local anesthetic or the like is added to the active ingredient of the invention, and injections for subcutaneous, intramuscular or intravenous administration can be formed in a conventional manner.
For formulering av suppositorier blir en base og om ønskelig, overflateaktive midler, tilsatt til det aktive ingredienset ifølge oppfinnelsen, og suppositorier blir fremstilt på konvensjonell måte. For the formulation of suppositories, a base and, if desired, surfactants are added to the active ingredient according to the invention, and suppositories are prepared in a conventional manner.
Eksipienter nyttige for faste preparater for oral administrering er de som generelt blir dannet innenfor fagområdet. Og nyttige eksempler er eksipienter så som laktose, sukrose, natriumklorid, stivelse, kalsiumkarbonat, kaolin, krystallinsk cellulose, metylcellulose, glycerin, natriumalginat, gummi arabikum og liknende, bindemidler så som polyvinylalkohol, polyvinyleter, polyvinylpyrrolidon, etylcellulose, gummi arabikum, skjellakk, sukrose, vann, etanol, prepanol, karboksymetylcellulose, kalsiumfosfat og liknende, smøremidler så som magnesiumstearat, talk og liknende, og innbefatter ytterligere additiver så som vanlig kjente farvemidler, oppløsnings-midler og liknende. Eksempler på baser nyttige for formulering av suppositorier er oljeholdige baser så som kakaosmør, polyetylenglykol, lanolin, fettsyretriglycerider, witepsol (varemerke, Dynamite Noel Co. Ltd.) og liknende. Flytende preparater kan være i form av vandige og oljeholdige suspensjoner, løsning, sirup, eliksir og liknende, som kan bli dannet på en konvensjonell måte ved anvendelse av additiver. Excipients useful for solid preparations for oral administration are those generally formed within the art. And useful examples are excipients such as lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, methyl cellulose, glycerin, sodium alginate, gum arabic and the like, binders such as polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, ethyl cellulose, gum arabic, shellac, sucrose , water, ethanol, prepanol, carboxymethyl cellulose, calcium phosphate and the like, lubricants such as magnesium stearate, talc and the like, and include further additives such as commonly known coloring agents, solvents and the like. Examples of bases useful for formulating suppositories are oily bases such as cocoa butter, polyethylene glycol, lanolin, fatty acid triglycerides, witepsol (trademark, Dynamite Noel Co. Ltd.) and the like. Liquid preparations can be in the form of aqueous and oily suspensions, solutions, syrups, elixirs and the like, which can be formed in a conventional way by using additives.
Mengde av forbindelse I ifølge oppfinnelsen inkorporert inn i den farmasøytiske sammensetningen ifølge oppfinnelsen varierer med doseringsform, oppløselighet og kjemiske egenskaper til forbindelsen, administreringsvei, administreringsskjema og liknende. Foretrukket at mengden er omtrernt 1 til 25 w/w% når det gjelder orale preparater, og omtrent 0,1 til 5 w/w% når det gjelder injeksjoner som er parenterale preparater. Amount of compound I according to the invention incorporated into the pharmaceutical composition according to the invention varies with dosage form, solubility and chemical properties of the compound, route of administration, administration schedule and the like. Preferably the amount is about 1 to 25 w/w% in the case of oral preparations, and about 0.1 to 5 w/w% in the case of injections which are parenteral preparations.
Dosering av forbindelse I ifølge oppfinnelsen blir bestemt på egnet måte avhengig av de individuelle tilfellene når det tas i betraktning så som symptomer, alder og kjønn til indiividet. Vanligvis er dosering når det gjelder oral administrering, omtrent 50 til 1500 mg pr. dag for en voksen i 2 til 4 oppdelte doser, og doseringen når det gjelder injeksjon, for eksempel ved intravenøs administrering, er 2 ml (omtrent 1 til 100 mg) som blir administrert en gang pr. dag for voksne hvori injeksjonen kan bli fortynnet med fysiologisk saltvann eller glukoseinjeksjonsvæske hvis det er ønskelig, og blir sakte administrert over minst 5 minutter. Dosering i tilfelle av suppositorier er omtrernt 1 til 1000 mg som blir administrert en eller to ganger pr. dag i et intervall på 6 til 12 timer hvor suppositoriene blir administrert ved innskudd i rektum. Dosage of compound I according to the invention is determined in a suitable manner depending on the individual cases when taking into account symptoms, age and gender of the individual. Generally, dosage for oral administration is about 50 to 1500 mg per day for an adult in 2 to 4 divided doses, and the dosage in terms of injection, for example by intravenous administration, is 2 ml (approximately 1 to 100 mg) which is administered once per day for adults in which the injection can be diluted with physiological saline or glucose solution for injection if desired, and is slowly administered over at least 5 minutes. Dosage in the case of suppositories is approximately 1 to 1000 mg which is administered once or twice per day. day in an interval of 6 to 12 hours where the suppositories are administered by insertion into the rectum.
Forbindelsene ifølge foreliggende oppfinnelse med formel I kan bli fremstilt ved omsetning av 3-aminoazetidin-2-onsulfonsyre med formel (II) med heteroarylkarboksylsyre med formel III etterfulgt av avbeskyttelse av beskyttelsesgruppen. The compounds according to the present invention with formula I can be prepared by reacting 3-aminoazetidin-2-one sulfonic acid with formula (II) with heteroarylcarboxylic acid with formula III followed by deprotection of the protecting group.
Visse derivater med generell formel IV ble fremstilt ved kopling av 3-aminoazetidin-2-onsulfonsyre (II) med en heteroarylkarboksylsyre (III) i nærvær av dicykloheksylkarbodiimid (DCC) eller med et syreklorid ifølge forbindelse (III) i nærvær av base, eller med en aktivert ester med forbindelse (III) som kjent innenfor fagområdet. Certain derivatives of general formula IV were prepared by coupling 3-aminoazetidin-2-onesulfonic acid (II) with a heteroarylcarboxylic acid (III) in the presence of dicyclohexylcarbodiimide (DCC) or with an acid chloride according to compound (III) in the presence of base, or with an activated ester with compound (III) as known in the art.
Altelrnativt kan forbindelsene med formel I også blir fremstilt som følger: Alternatively, the compounds of formula I can also be prepared as follows:
Fremstilling av forbindelse II (R= CH3) kan bli utført ved å følge synteseskjema 2 sorri beskrevet i J. Org. Chem. 1982, 47, 5160-5167. Preparation of compound II (R=CH3) can be carried out by following synthesis scheme 2 sorri described in J. Org. Chem. 1982, 47, 5160-5167.
Fremstilling av forbindelse II (R=CH2F, CH2OCONH2) ble utført ved å følge synteseskjema 3 fra felles mellomproduktforbindelse V som beskrevet i J. Antibiotics 1985, 36, 1201-1204 og J. Antibiotics 1985, 38, 346-357. Preparation of compound II (R=CH 2 F, CH 2 OCONH 2 ) was carried out by following synthetic scheme 3 from common intermediate compound V as described in J. Antibiotics 1985, 36, 1201-1204 and J. Antibiotics 1985, 38, 346-357.
Felles mellomproduktforbindelse V ble fremstilt ved å følge synteseveier» som beskrevet i skjema 4. Distereoisimerer av forbindelse VI blir separert ved optiske reduksjonsmetoder (J. Antibiotics 1985, 38, 346). Common intermediate compound V was prepared by following synthetic routes' as described in Scheme 4. Distereoisomers of compound VI are separated by optical reduction methods (J. Antibiotics 1985, 38, 346).
Fremstilling av forbindelsene III ble utført ved omsetning av 2-heteroaryl-2-okso eddiksyre (VII) med O-herteroarylhydroksylamin (VIII) ved romtemperatur og ga ekslusitvt Syn isomer. Fremstilling av forbindelse VIII ble utført som beskrevet i skjema 5 begynnende fra heteroarylmetanol (J. Antibiotics 1990, 43, 189-198). Preparation of the compounds III was carried out by reacting 2-heteroaryl-2-oxo acetic acid (VII) with O-heteroarylhydroxylamine (VIII) at room temperature and gave exclusively the Syn isomer. Preparation of compound VIII was carried out as described in Scheme 5 starting from heteroarylmethanol (J. Antibiotics 1990, 43, 189-198).
DEAD = dietylazodikarboksylat DEAD = diethyl azodicarboxylate
I ovennevnte beskrivelser (skjema 1-5) blir reaktantene reagert sammen med et egnet løsningsmiddel ved forhøyete eller lave temperaturer i tilstrekkelig tidspunkt for å muliggjøre at reaksjonen går fullstendig. Reaksjonsbetingelsene vil avhenge av naturen og reaktiviteten til reaktantene. Når en base blir anvendt i en reaksjon, blir de valgt fra trietylamin, tributylamin, trioktylamin, pyridin, 4-dimetylaminopyridin, diisopropyletylamin, 1,5-diazabicyklo[4,3]non-5-en, 1,8-diazabicyklo[5,4,0]undek-7-en, natriumkarbonat, natriumbikarbonat, kaliumkarbonat, kaliumbikaronat og sesiumkarbonat. In the above descriptions (schemes 1-5), the reactants are reacted together with a suitable solvent at elevated or low temperatures for a sufficient time to enable the reaction to proceed completely. The reaction conditions will depend on the nature and reactivity of the reactants. When a base is used in a reaction, they are selected from triethylamine, tributylamine, trioctylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, 1,5-diazabicyclo[4,3]non-5-ene, 1,8-diazabicyclo[5 ,4,0]undec-7-ene, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and cesium carbonate.
Avbeskyttelse av beskyttelsesgruppen blir utført enten ved hydrogenering eller ved hydrolyse med hensiktsmessige syrer så som saltsyre, trifluoreddiksyre eller eddiksyre i et løsningsmiddel så som metanol, etanol, propanol eller etylacetat. Hydrogeneringsreaksjonen blir vanligvis utført i nærvær av en metallkatalysator, så som Pd, Pt eller Rh, under normalt trykk til høy temperatur. Deprotection of the protecting group is carried out either by hydrogenation or by hydrolysis with appropriate acids such as hydrochloric acid, trifluoroacetic acid or acetic acid in a solvent such as methanol, ethanol, propanol or ethyl acetate. The hydrogenation reaction is usually carried out in the presence of a metal catalyst, such as Pd, Pt or Rh, under normal pressure at high temperature.
Valg av løsningsmidler for reaksjonen blir valgt basert på reaktanter som blir anvendt og fra slike løsningsmidler som benzen, toluen, acetonitril, tetrahydrofuran, etanol, metanol, kloroform, etylacetat, metylenklorid, dimetylformamid, dimetylsulfoksid, heksametylfosforsyretriamid eller liknende. Løsningsmiddel-blandinger kan også bli anvendt. Solvents for the reaction are selected based on the reactants used and from such solvents as benzene, toluene, acetonitrile, tetrahydrofuran, ethanol, methanol, chloroform, ethyl acetate, methylene chloride, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric acid triamide or the like. Solvent mixtures can also be used.
Reaksjonstemperaturer varierer generelt fra mellom -70°C til 150 °C. Foretrukne morale forhold av reaktantene er 1:1 til 1:5. Reaksjonstiden varierer fra 0,5 til 72 timer avhengig av rektantene. Reaction temperatures generally range from between -70°C to 150°C. Preferred molar ratios of the reactants are 1:1 to 1:5. The reaction time varies from 0.5 to 72 hours depending on the rectants.
Foreliggende oppfinnelse blir videre illustrert i følgende eksempler. The present invention is further illustrated in the following examples.
Eksempel 1 Example 1
(3S)-trans-3-[(2-aminop)tiazol-4-yl)-(Z)-2-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-metyl-2-oksoazetidin-1-sulfonsyre, natriumsalt, Trinn 1: 1,5-dibenzhydryloksy-2-(N-ftalimido)oksymetyl-4-pyridon (3S)-trans-3-[(2-aminop)thiazol-4-yl)-(Z)-2-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)imino}acetamido]-4- methyl-2-oxoazetidine-1-sulfonic acid, sodium salt, Step 1: 1,5-dibenzhydryloxy-2-(N-phthalimido)oxymethyl-4-pyridone
En løsning av 1,5-dibenzhydryloksy-2-hydroksymetyl-4-pyridon (20,0 g, A solution of 1,5-dibenzhydryloxy-2-hydroxymethyl-4-pyridone (20.0 g,
0,041 mol) og N-hydroksyftatimid (6,64 g, 0,048 mol) i en blanding av THF (200 ml) og tørr DMF (200 ml) ble behandlet med trifenylfosfen under nitrogen og avkjølt til 0°C. Reaksjonsblandingen ble deretter tilsatt med dietylazodikarboksylat dråpevis over 10 min, omrørt ved 0°C i 1 t og deretter fortynnet med etylacetat og vann. Det organiske laget ble separert, vasket med vann og saltvann, tørket over natriumsulfat, filtrert og avdampet / vakuum. Det oppnådde råproduktet ble renset ved silikagelkolonnekromatografi ved anvendelse av en gradientblanding bestående av EA:heksan (1:2 til 1:0) for å gi den rene tittelforbindelsen. 0.041 mol) and N-hydroxyphtatimide (6.64 g, 0.048 mol) in a mixture of THF (200 mL) and dry DMF (200 mL) were treated with triphenylphosphene under nitrogen and cooled to 0 °C. The reaction mixture was then added with diethyl azodicarboxylate dropwise over 10 min, stirred at 0°C for 1 h and then diluted with ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered and evaporated/vacuum. The obtained crude product was purified by silica gel column chromatography using a gradient mixture consisting of EA:hexane (1:2 to 1:0) to give the pure title compound.
Utbytte: 19,0 g, 73% Yield: 19.0 g, 73%
<1>HNMR (DMSO-de): 8 4,78 (s, 2H), 6,24 (s, 1H), 6,29 (s, 1H), 6,46 (s, 1H), 7,18-7,38 (m, 20 H), 7,62 (s, 1H), 7,85 (s, 4H). <1>HNMR (DMSO-de): δ 4.78 (s, 2H), 6.24 (s, 1H), 6.29 (s, 1H), 6.46 (s, 1H), 7.18 -7.38 (m, 20H), 7.62 (s, 1H), 7.85 (s, 4H).
Trinn 2: 2-(2-tritylamino)-tiazol-4-yl)-(Z)-2-[1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksyj-imino eddiksyre. Step 2: 2-(2-Tritylamino)-thiazol-4-yl)-(Z)-2-[1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy-imino acetic acid.
En løsning av 1,5-dibenzhydryloksy-2-(N-ftalimio)oksymetyl-4-pyridon (10 g, 15,8 mmol) i etanol (98%, 100 ml) ble behandlet med hydrazin (0,76 ml). Blandingen ble oppvarmet til tilbakeløp i 1 t og avkjølt til RT. Suspensjonen som dermed ble oppnådd ble filtrert, og filtratet ble avdampet til tørrhet og ble behandlet ble kloroform. Faststoffet som dermed ble separert, ble filtrert ut, morvæskene ble konsentrert, og resten som ble oppnådd, ble oppløst i etanol (98%) og deretter behandlet med en løsning av 2-okso-(2-[(N-tritylamino)tiazol-5-yl]eddiksyre (6,38 g) i kloroform. Reaksjonsblandingen ble omrørt ved romtemperatur i 18 t og avdampet i vakuum. Resten som ble oppnådd, ble løst opp i etylacetat og fortynnet med heksaner. Det separerte faststoffet ble filtrert og tørket for å gi 2-(2-tritylamino)tiazol-4-yl)-(Z)-2-[1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy]imino eddiksyre. A solution of 1,5-dibenzhydryloxy-2-(N-phthalimio)oxymethyl-4-pyridone (10 g, 15.8 mmol) in ethanol (98%, 100 mL) was treated with hydrazine (0.76 mL). The mixture was heated to reflux for 1 h and cooled to RT. The suspension thus obtained was filtered, and the filtrate was evaporated to dryness and treated with chloroform. The solid thus separated was filtered off, the mother liquors were concentrated, and the residue obtained was dissolved in ethanol (98%) and then treated with a solution of 2-oxo-(2-[(N-tritylamino)thiazole- 5-yl]acetic acid (6.38 g) in chloroform. The reaction mixture was stirred at room temperature for 18 h and evaporated in vacuo. The residue obtained was dissolved in ethyl acetate and diluted with hexanes. The separated solid was filtered and dried for to give 2-(2-tritylamino)thiazol-4-yl)-(Z)-2-[1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy]imino acetic acid.
Utbytte: 11,2 g, 79% Yield: 11.2 g, 79%
<1>HNMR (DMSO-de): 8 4,62 (s, 2H), 6,03 (s, 1H), 6,28 (s, 1H), 6,40 (s, 1H), 6,66 (s, 1H), 7,18-7,35 (m, 35H), 7,48 (s, 1H), 8,64 (s, 1H). <1>HNMR (DMSO-de): δ 4.62 (s, 2H), 6.03 (s, 1H), 6.28 (s, 1H), 6.40 (s, 1H), 6.66 (s, 1H), 7.18-7.35 (m, 35H), 7.48 (s, 1H), 8.64 (s, 1H).
Trinn 3: (3S)-trans-3-[2-(2-tritylamino)tiazol-4-yl)-(Z)-2-{(1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-metyl-2-oksoazetidin-1-sulfonsyre. Step 3: (3S)-trans-3-[2-(2-tritylamino)thiazol-4-yl)-(Z)-2-{(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy)imino} acetamido]-4-methyl-2-oxoazetidine-1-sulfonic acid.
En blanding av (3S)-trans-3-amino-4-metyl-2-oksoazetidin-1-sulfonsyre [7,30 g, 40,52 mmol, J. Org. Chem., 47, 5160, (1982)], 2-(2-tritylamino)tiazol-4-yl)-(Z)-2-[(1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy]imino eddiksyre (fra trinn 36,50 g. 40,51 mmol) DCC (9,15 g, 44,34 mmol) og 1-hydroksybenzotriazol (5,47 g, A mixture of (3S)-trans-3-amino-4-methyl-2-oxoazetidine-1-sulfonic acid [7.30 g, 40.52 mmol, J. Org. Chem., 47, 5160, (1982)], 2-(2-tritylamino)thiazol-4-yl)-(Z)-2-[(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy]imino acetic acid (from step 36.50 g, 40.51 mmol) DCC (9.15 g, 44.34 mmol) and 1-hydroxybenzotriazole (5.47 g,
40,5 mmol) i tørr DMF (400 ml) ble omrørt ved romtemperatur i 30 min, og til denne blandingen ble NaHC03 (3,40 g, 40,52 mmol) tilsatt. Blandingen ble omrørt under nitrogen ved romtemperatur over natt og filtrert. Morvæsken ble avdampet /' vakuum for å fjerne DMF, og resten som ble oppnådd, ble løst opp i etylacetat og destillert vann og justert til pH ~3. Det organiske laget ble tørket over vannfri natriumsulfat, filtrert og avdampet /' vakuum. 40.5 mmol) in dry DMF (400 mL) was stirred at room temperature for 30 min, and to this mixture NaHCO 3 (3.40 g, 40.52 mmol) was added. The mixture was stirred under nitrogen at room temperature overnight and filtered. The mother liquor was evaporated /' vacuum to remove DMF and the residue obtained was dissolved in ethyl acetate and distilled water and adjusted to pH ~3. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under vacuum.
Produktet oppnådd på denne måten ble renset over HP-20 kolonnekromatografi ved anvendelse av en gradientblanding bestående av vann:acetonitril (1:0 til 1:9) for å gi tittelforbindelsen. Silikagelkolonnekromatografi ved anvendelse av en gradientblanding bestående av etylacetat:metanol (1:0 til 9:1) ga tittelforbindelsen. The product thus obtained was purified over HP-20 column chromatography using a gradient mixture consisting of water:acetonitrile (1:0 to 1:9) to give the title compound. Silica gel column chromatography using a gradient mixture of ethyl acetate:methanol (1:0 to 9:1) afforded the title compound.
Utbytte: 37,00 g, 85,9% Yield: 37.00 g, 85.9%
<1>HNMR (DMSO-de): 5 1,29 (d, 3H, J=6,9 Hz), 3,54-3,61 (m, 1H), 4,30-4,35 (m, 1H), 4,70 (s, 2H), 5,98 (s, 1H), 6,29 (s, 2H), 6,71 (s, 1H), 7,25-7,35 (m, 35H), 7,51 (s, 1H), 8,83 (s, 1H), 9,39 (d, 1H, J=7,7 Hz). <1>HNMR (DMSO-de): δ 1.29 (d, 3H, J=6.9 Hz), 3.54-3.61 (m, 1H), 4.30-4.35 (m, 1H), 4.70 (s, 2H), 5.98 (s, 1H), 6.29 (s, 2H), 6.71 (s, 1H), 7.25-7.35 (m, 35H ), 7.51 (s, 1H), 8.83 (s, 1H), 9.39 (d, 1H, J=7.7 Hz).
Trinn 4: (3S)-trans-3-[(2-amino)(tiazol-4-yl)-(Z)-2-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)am i nojacetam ido]-4-metyl2-oksoazetid in-1 -su lfonsyre. Step 4: (3S)-trans-3-[(2-amino)(thiazol-4-yl)-(Z)-2-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)am in nojacetam ido]-4-methyl2-oxoazetide in-1-sulfonic acid.
En suspensjon av (3S)-trans-3-[2-(2-tritylamino)tiazol-4-yl)-(Z)2-{(1,5- A suspension of (3S)-trans-3-[2-(2-tritylamino)thiazol-4-yl)-(Z)2-{(1,5-
dibenzhydryloksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-metyl-2-oksoazetidin-1-sulfonsyre (5,00 g, 4,703 mmol) i tørr anisol (14 ml) ved -10°C under nitrogen ble behandlet med trifluoreddiksyre (25 ml) og omrørt ved 0°C i 2 t. Løsningsmidlene ble Dibenzhydryloxy-4-pyridon-2-ylmethoxy)imino}acetamido]-4-methyl-2-oxoazetidine-1-sulfonic acid (5.00 g, 4.703 mmol) in dry anisole (14 mL) at -10°C under nitrogen was treated with trifluoroacetic acid (25 ml) and stirred at 0°C for 2 h. The solvents were
avdampet under redusert trykk, og resten ble triturert med en blanding av eterheksan og etylacetat (1:1:1). Faststoffet dermed oppnådd ble filtrert, vasket med en blanding av eter-heksan og etylacetat (1:1:1) for å gi et faststoff. Ovennevnte faststoff ble videre renset ved HP-20 kolonnekromatografi ved anvendelse av engradientblanding av destillert vann og acretonitril (1:0 til 9:1), og hensiktsmessige fraksjoner ble lyofilisert for å gi tittelforbindelsen. evaporated under reduced pressure, and the residue was triturated with a mixture of etherhexane and ethyl acetate (1:1:1). The solid thus obtained was filtered, washed with a mixture of ether-hexane and ethyl acetate (1:1:1) to give a solid. The above solid was further purified by HP-20 column chromatography using a gradient mixture of distilled water and acretonitrile (1:0 to 9:1), and appropriate fractions were lyophilized to give the title compound.
Utbytte: 2,7 g, 92%; smp: 200°C dekomp. Yield: 2.7 g, 92%; mp: 200°C decomp.
<1>HNMR (DMSO-de): 5 1,41 (d, 3H, J=6,2 Hz), 3,70-3,80 (m, 1H), 4,46 (dd, 1H, J=2,4 Hz og 5,2 Hz), 5,30 (s, 2H), 6,85 (s, 1H), 7,05 (s, 1H), 7,35 (br, s, 2H), 8,17 (s, 1H), 9,50 (d, 1H, J=7,7 Hz). <1>HNMR (DMSO-de): δ 1.41 (d, 3H, J=6.2 Hz), 3.70-3.80 (m, 1H), 4.46 (dd, 1H, J= 2.4 Hz and 5.2 Hz), 5.30 (s, 2H), 6.85 (s, 1H), 7.05 (s, 1H), 7.35 (br, s, 2H), 8 .17 (s, 1H), 9.50 (d, 1H, J=7.7 Hz).
Trinn 5: (3S)-trans 3-[(2-amino)tiazol-4-yl)-(Z)-2-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}acetamidol-4-metyl-2-oksazetidin-1-sulfonsyre, natriumsalt. Step 5: (3S)-trans 3-[(2-amino)thiazol-4-yl)-(Z)-2-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)imino}acetamidol-4 -methyl-2-oxazetidine-1-sulfonic acid, sodium salt.
En suspensjon av (3S)-trans-3-[(Z)-(2-amino)tiazol-4-yl)-2-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-metyl-2-oksoazetidin-1-sulfonsyre (1,30 g, 2,66 mmol) I destillert vann (15 ml) ble avkjølt til ~5-6°C og NaHC03 (s, 0,223 g, 2,654 mmol) ble tilsatt I porsjoner med omrøring. Den klare løsningen dermed oppnådd I løpet av 10 min. ble filtrert og lyofilisert for å gi (3S)-trans-3-[(2-amino)tiazol-4-yl)-(Z)-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-metyl-2-oksoazetidin-1 -sulfonsyre, natriumsalt. A suspension of (3S)-trans-3-[(Z)-(2-amino)thiazol-4-yl)-2-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)imino}acetamido] -4-Methyl-2-oxoazetidine-1-sulfonic acid (1.30 g, 2.66 mmol) In distilled water (15 mL) was cooled to ∼5-6 °C and NaHCO 3 (s, 0.223 g, 2.654 mmol) was added in portions with stirring. The clear solution thus achieved Within 10 min. was filtered and lyophilized to give (3S)-trans-3-[(2-amino)thiazol-4-yl)-(Z)-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)imino} acetamido]-4-methyl-2-oxoazetidine-1-sulfonic acid, sodium salt.
Utbytte: 1,32 g, 97,13%. Yield: 1.32 g, 97.13%.
<1>HNMR (DMSO-de): 5 1,42 (d, 3H, J=6,1 Hz), 3,70-3,80 (m, 1H), 4,48-4,53 (m, 1H), 5,13 (s, 2H), 6,64 (s, 1H), 6,79 (s, 1H), 7,24 (br, s, 2H), 7,68 (s, 1H), 9,52 (d, 1H, J=7,0 Hz). <1>HNMR (DMSO-de): δ 1.42 (d, 3H, J=6.1 Hz), 3.70-3.80 (m, 1H), 4.48-4.53 (m, 1H), 5.13 (s, 2H), 6.64 (s, 1H), 6.79 (s, 1H), 7.24 (br, s, 2H), 7.68 (s, 1H), 9.52 (d, 1H, J=7.0 Hz).
Eksempel 2 Example 2
3-[2-(2-aminotiazol-4-yl)-(Z)-2-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}-acetamido]-4-karbamoyloksymetyl-2-azetidinon-1-sulfonsyre, natriumsalt Trinn 1: 3-[2-(2-tritylamino)-tiazol-4-yl)-(Z)-{(1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-karbamoyloksymetyl-2-azetidinon 3-[2-(2-aminothiazol-4-yl)-(Z)-2-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)imino}-acetamido]-4-carbamoyloxymethyl-2-azetidinone -1-sulfonic acid, sodium salt Step 1: 3-[2-(2-tritylamino)-thiazol-4-yl)-(Z)-{(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy)imino}acetamido ]-4-carbamoyloxymethyl-2-azetidinone
En løsning av 2-(2-tritylamino)-tiazol-4-yl)-(Z)-2-[1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy]imino eddiksyre (0,34 g, 0377 mmol) i tørr DMF (20 ml) ble behandlet med DCC (0,078 g, 0,37 mmol) og 1-hydroksybenzotriazol (0,050 g, 0,0377 mmol). Blandingen ble omrørt under nitrogen ved romtemperatur i 30 min, og denne blandingen ble NaHC03 (0,032 g, 0,377 mmol) og 3-amino-4-karbamoyloksymetyl-2-azetidinon (0,06 g, 0,377 mmol) i DMF (5 ml) tilsatt. Reaksjonsblandingen ble omrørt ved romtemperatur i 181, og DMF ble fjernet / vakuum. Produktet oppnådd på denne måten ble renset ved silikagelkolonnekromatografi ved en gradientblanding av etylacetat og metanol (10:1 til 9,5:0,5) for å gi tittelforbindelsen. A solution of 2-(2-tritylamino)-thiazol-4-yl)-(Z)-2-[1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy]imino acetic acid (0.34 g, 0377 mmol) in dry DMF (20 mL) was treated with DCC (0.078 g, 0.37 mmol) and 1-hydroxybenzotriazole (0.050 g, 0.0377 mmol). The mixture was stirred under nitrogen at room temperature for 30 min, and this mixture was NaHCO 3 (0.032 g, 0.377 mmol) and 3-amino-4-carbamoyloxymethyl-2-azetidinone (0.06 g, 0.377 mmol) in DMF (5 mL) added. The reaction mixture was stirred at room temperature for 181, and the DMF was removed / vacuum. The product thus obtained was purified by silica gel column chromatography using a gradient mixture of ethyl acetate and methanol (10:1 to 9.5:0.5) to give the title compound.
Utbytte: 0,2 g, 97,13% Yield: 0.2 g, 97.13%
<1>HNMR (DMSO-de): 8 3,80-3,92 (m, 2H), 3,97-4,05 (m, 1H), 4,70 (s, 2H), 5,17-5,25 (m, 1H), 6,00 (s, 1H), 6,31 (s, 1H), 6,53 (br, s, 2H), 6,74 (s, 1H), 7,24-7,38 (m, 35H), 7,58 (s, 1H), 8,50 (s, 1H), 8.80 (s, 1H), 9,29 (d, 1H, J=9,0 Hz). <1>HNMR (DMSO-de): δ 3.80-3.92 (m, 2H), 3.97-4.05 (m, 1H), 4.70 (s, 2H), 5.17- 5.25 (m, 1H), 6.00 (s, 1H), 6.31 (s, 1H), 6.53 (br, s, 2H), 6.74 (s, 1H), 7.24 -7.38 (m, 35H), 7.58 (s, 1H), 8.50 (s, 1H), 8.80 (s, 1H), 9.29 (d, 1H, J=9.0 Hz) .
Trinn 2: 3-[{2-(2-tritylamino)tiazol-4-yl)}-(Z)-2-{(1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-karbamoyloksymetyl-2-azetidinon-1-sulfonsyre Step 2: 3-[{2-(2-Tritylamino)thiazol-4-yl)}(Z)-2-{(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy)imino}acetamido]-4 -carbamoyloxymethyl-2-azetidinone-1-sulfonic acid
En løsning av 3-[{2-(2-tritylamino)tiazol-4-yl)}-(Z)-2-[(1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-karbamoyloksymetyl-2-azetidinon (0,25 g, 0,244 mmol) I pyridin (2 ml) ble behandlet med svoveltrioksidpyridinkompleks (0,153 g, 0,96 mmol), og blandingen ble oppvarmet ved 70°C I 45 min. Reaksjonsblandingen ble avkjølt til RT, behandelt med dietyleter, og faststoffet ble filtrert, vasket med destillert vann etterfulgt av eter og tørket for å gi ciss-3-[{2-(2-tritylamino)tiazol-4-yl)}-(Z)-2-{(1,5-dibemzhydryloksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-karbamoyloksymetyl-2-azetidinon-1-svovelsyre. A solution of 3-[{2-(2-tritylamino)thiazol-4-yl)}(Z)-2-[(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy)imino}acetamido]-4 -carbamoyloxymethyl-2-azetidinone (0.25 g, 0.244 mmol) in pyridine (2 mL) was treated with sulfur trioxide pyridine complex (0.153 g, 0.96 mmol) and the mixture was heated at 70°C for 45 min. The reaction mixture was cooled to RT, treated with diethyl ether, and the solid was filtered, washed with distilled water followed by ether and dried to give ciss-3-[{2-(2-tritylamino)thiazol-4-yl)}(Z )-2-{(1,5-dibemzhydryloxy-4-pyridon-2-ylmethoxy)imino}acetamido]-4-carbamoyloxymethyl-2-azetidinone-1-sulfuric acid.
Utbytte: 0,23 g, 85% Yield: 0.23 g, 85%
Trinn 3: 3-[2-(2-tritylamino)-tiazol-4-yl)-(Z)-2-{(1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-karbamoyloksymetyl-2-azetidinon-1-sulfonsyre, natriumsalt. Step 3: 3-[2-(2-tritylamino)-thiazol-4-yl)-(Z)-2-{(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy)imino}acetamido]-4- carbamoyloxymethyl-2-azetidinone-1-sulfonic acid, sodium salt.
En suspensjon av 3-[2-(2-tritylamino)-tiazol-4-yl-(Z)-2-{(1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-karbamoyloksymetyl-2-azetidinon-1-sulfonsyre (0,390 g, 0,353 mmol) i destillert vann (10 ml) ble behandlet med NaHC03 (s, 0,050 g, 0,595 mmol) og omrørt ved RT i 30 min, og den klare løsningen ble lyofilisert. Det oppnådde faststoffet ble renset ved HP-20 kolonnekromatografi ved anvendelse av en gradientblanding av dd.vann og acetonitril (1:0 til 3:7), og hensiktsmessige fraksjoner ble lyofilisert for å gi 3-[2-(2-tritylamino)-tiazol-4-yl)-(Z)-2-{(1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-karbamoyloksymetyl-2-azetidinon-1 -sulfonsyre, natriumsalt. A suspension of 3-[2-(2-tritylamino)-thiazol-4-yl-(Z)-2-{(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy)imino}acetamido]-4-carbamoyloxymethyl -2-Azetidinone-1-sulfonic acid (0.390 g, 0.353 mmol) in distilled water (10 mL) was treated with NaHCO 3 (s, 0.050 g, 0.595 mmol) and stirred at RT for 30 min, and the clear solution was lyophilized. The obtained solid was purified by HP-20 column chromatography using a gradient mixture of distilled water and acetonitrile (1:0 to 3:7), and appropriate fractions were lyophilized to give 3-[2-(2-tritylamino)- thiazol-4-yl)-(Z)-2-{(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy)imino}acetamido]-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid, sodium salt.
Utbytte: 0,21 g, 52% Yield: 0.21 g, 52%
Trinn 4: 3-[2-(2-aminotiazol-4-yl)-(Z)-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-karbamoyloksymetyl-2-azetidinon-1-sulfonsyre. Step 4: 3-[2-(2-aminothiazol-4-yl)-(Z)-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)imino}acetamido]-4-carbamoyloxymethyl-2-azetidinone -1-sulfonic acid.
En suspensjon av 3-[2-tritylamino)tiazol-4-yl)-(Z)-2-{(1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-karbamoyloksymetyl-2-azetidinon-1-sulfonsyre, natriumsalt (0,8 g, 0,874 mmol) i anisol (5 ml) under nitrogenatmosfære ble avkjølt til ~0°C og behandlet med trifuloreddiksyre (25 ml), og blandingen ble omrørt ved mindre enn 10°C i 21 og behandlet med eter. Det separerte faststoffet ble filtrert, vasket med aceton og oppløst i en blanding av acetonitril/dd. H20 og frysetørket for å gi tittelforbindelsen. A suspension of 3-[2-tritylamino)thiazol-4-yl)-(Z)-2-{(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy)imino}acetamido]-4-carbamoyloxymethyl-2- Azetidinone-1-sulfonic acid, sodium salt (0.8 g, 0.874 mmol) in anisole (5 mL) under nitrogen atmosphere was cooled to ∼0 °C and treated with trifluoroacetic acid (25 mL), and the mixture was stirred at less than 10 °C in 21 and treated with ether. The separated solid was filtered, washed with acetone and dissolved in a mixture of acetonitrile/dd. H 2 O and freeze-dried to give the title compound.
Utbytte: 0,34 g, 89%; smp: 190° dekomp. Yield: 0.34 g, 89%; mp: 190° decomp.
<1>HNMR (DMSO-de): 5 3,90-4,30 (m, 3H), 5,22-5,40 (m, 5H), 6,50 (br, s, 2H), 6,82 (s, 1H), 6,95 (s, 1H), 7,33 (br, s, 2H), 8,00 (s, 1H), 9,45 (d, 1H, J=7,5 Hz). <1>HNMR (DMSO-de): δ 3.90-4.30 (m, 3H), 5.22-5.40 (m, 5H), 6.50 (br, s, 2H), 6, 82 (s, 1H), 6.95 (s, 1H), 7.33 (br, s, 2H), 8.00 (s, 1H), 9.45 (d, 1H, J=7.5 Hz ).
Trinn 5: 3-[2-(2-aminotiazol-4-yl)-(Z)-2-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-karbamoyloksymetyl-2-azetidinon-1-sulfonsyre, natriumsalt Step 5: 3-[2-(2-aminothiazol-4-yl)-(Z)-2-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)imino}acetamido]-4-carbamoyloxymethyl-2 -azetidinone-1-sulfonic acid, sodium salt
NaHC03 (s, 6 mg, 0,073 mmol) ble tilsatt til en suspensjon av 3-[2-(2-aminotiazol-4-yl)-(Z)-2-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}-acetamido]-4-karbamoyloksymetyl-2-azetidinon-1-sulfonsyre (40 mg, 0,073 mmol) I destillert vann. Etter omrøring I 5 min ble blandingen frysetørket for å gi tittelforbindelsen som et faststoff. NaHCO 3 (s, 6 mg, 0.073 mmol) was added to a suspension of 3-[2-(2-aminothiazol-4-yl)-(Z)-2-{(1,5-dihydroxy-4-pyridon-2 -ylmethoxy)imino}-acetamido]-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid (40 mg, 0.073 mmol) in distilled water. After stirring for 5 min, the mixture was freeze-dried to give the title compound as a solid.
Utbytte: 30 mg, 71% Yield: 30 mg, 71%
<1>HNMR (DMSO-de): 8 4,03-4,15 (m, 2H), 4,20-4,33 (m, 1H), 5,12 (s, 2H), 5,26-5,37 (m, 1H), 6,54 (br, s, 2H), 6,70 (s, 1H), 6,77 (s, 1H), 7,24 (br, s, 2H), 7,72 (s, 1H), 9,38 (d, 1H, J=7,5Hz). <1>HNMR (DMSO-de): δ 4.03-4.15 (m, 2H), 4.20-4.33 (m, 1H), 5.12 (s, 2H), 5.26- 5.37 (m, 1H), 6.54 (br, s, 2H), 6.70 (s, 1H), 6.77 (s, 1H), 7.24 (br, s, 2H), 7 .72 (s, 1H), 9.38 (d, 1H, J=7.5Hz).
Eksempel 3 Example 3
3-[2-(2-aminotiazol-4-yl)-(Z)-2-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}-acetamido]-4-fluormetyl-2-azetidinon-1 -sulfonsyre, natriumsalt 3-[2-(2-aminothiazol-4-yl)-(Z)-2-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)imino}-acetamido]-4-fluoromethyl-2-azetidinone -1 -sulfonic acid, sodium salt
Trinn 1: 3-[2-(2-tritylamino)-tiazol-4-yl)-(Z)-2-{(1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy)imino}acetamido}-4-fluormetyl-2-azetidinon-1-sulfonsyre. Step 1: 3-[2-(2-tritylamino)-thiazol-4-yl)-(Z)-2-{(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy)imino}acetamido}-4- fluoromethyl-2-azetidinone-1-sulfonic acid.
En løsning av 3-(N-benzyloksykarbonyl)amino-4-fluormetyl-2-azetidinon-1-sulfonsyre, tetrabutylammoniumsalt (0,5 g, 0,89 mmol) I DMF (20 m) ble behandlet med Pd-C (0,3 g), og suspensjonen ble hydrogenert ved 50 psi I over 5 t. Suspensjonen ble filtrert gjennom celitt, og til iltratet ble det tilsatt DCC (0,18 g, 0,89 mmol), 1-HBT (0,12 g, 0,89 mmol) etterfulgt av 2-{(2-tritylamino)-tiazol-4-yl}-(Z)-[1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy]iminoeddiksyre (0,4 g, 0,89 mmol). Reaksjonsblandingen ble omrørt ved RT I 181 og avdampet I vacuum. Resten ble løst opp i aceton og behandlet med kaliumnonafluorborat (0,6 g) i aceton og omrørt i ytterligere 181. Løsningsmidlene ble avdampet, og resten ble behandlet med en blanding av etylacetat-eterheksan (1:1:1). Det separerte faststoffet ble filtrert og renset ved silikagelkolonnekromatografi ved anvendelse av en gradientblanding av etylacetat og metanol (10:1 til 9:1) for å gi tittelforbindelsen. A solution of 3-(N-benzyloxycarbonyl)amino-4-fluoromethyl-2-azetidinone-1-sulfonic acid, tetrabutylammonium salt (0.5 g, 0.89 mmol) in DMF (20 m) was treated with Pd-C (0 .3 g), and the suspension was hydrogenated at 50 psi I over 5 h. The suspension was filtered through celite, and to the nitrate was added DCC (0.18 g, 0.89 mmol), 1-HBT (0.12 g , 0.89 mmol) followed by 2-{(2-tritylamino)-thiazol-4-yl}(Z)-[1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy]iminoacetic acid (0.4 g, 0.89 mmol). The reaction mixture was stirred at RT 181 and evaporated in vacuo. The residue was dissolved in acetone and treated with potassium nonafluoroborate (0.6 g) in acetone and stirred for an additional 181. The solvents were evaporated and the residue was treated with a mixture of ethyl acetate-etherhexane (1:1:1). The separated solid was filtered and purified by silica gel column chromatography using a gradient mixture of ethyl acetate and methanol (10:1 to 9:1) to give the title compound.
Utbytte: 0,22 g, 42,8% Yield: 0.22 g, 42.8%
<1>HNMR (DMSO-de): 8 4,00-4,20 (m, 2H), 4,40-4,50 (m, 1H), 4,67 (s, 2H), 5,16-5,24 (m, 1H), 6,00 (s, 1H), 6,32 (s, 1H), 6,37 (s, 1H), 6,67 (s, 1H), 7,27-7,43 (m, 35H), 7,63 (s, 1H), 8,85 (s, 1H), 9,46 (d, 1H, J=9,0 Hz). <1>HNMR (DMSO-de): δ 4.00-4.20 (m, 2H), 4.40-4.50 (m, 1H), 4.67 (s, 2H), 5.16- 5.24 (m, 1H), 6.00 (s, 1H), 6.32 (s, 1H), 6.37 (s, 1H), 6.67 (s, 1H), 7.27-7 .43 (m, 35H), 7.63 (s, 1H), 8.85 (s, 1H), 9.46 (d, 1H, J=9.0 Hz).
Trinn 2: 3-[2-(2-aminotiazol-4-yl)-(Z)-2-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-fluormetyl-2-azetidinon-1-sulfonsyre, natriumsalt. Step 2: 3-[2-(2-aminothiazol-4-yl)-(Z)-2-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)imino}acetamido]-4-fluoromethyl-2 -azetidinone-1-sulfonic acid, sodium salt.
En suspensjon av 3-[2-(2-tritylamino)tiazol-4-yl)-(Z)-2-{(1,5-dibenzhydryloksy-4-pyridon-2-ylmetoksy)imino}acetamido]-4-fluormetyl-2-azetidinon-1-sulfonsyre (0,5 g, 0,46 mmol) I anisol (2 ml) under nitrogen ved -10°C ble behandlet med trifluoreddiksyre (20 ml) og omrørt ved 5-10°C I 2 t. Reaksjonsblandingen ble avdampet / vacuum, og resten ble triturert med en blanding av etenetylacetat og heksaner (1:1:1). Det separerte faststoffet ble filtrert, oppløst i acetonitril, vannblanding og frysetørket. Det oppnådde råproduktet ble ytterligedre renset ved HP-20 kolonnekromatografi ved anvendelse av en gradientblanding av dd.H20 og acetonitril (1:0 til 9,4:0,6) for å gi 3-[2-(2-aminotiazol-4-yl)-(Z)-2-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}-acetamido]-4-fluormetyl-2-acetidinon-1-sulfonsyre. Utbytte: 80 mg, 34%; smpt: 200°C dekomp. A suspension of 3-[2-(2-tritylamino)thiazol-4-yl)-(Z)-2-{(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxy)imino}acetamido]-4-fluoromethyl -2-Azetidinone-1-sulfonic acid (0.5 g, 0.46 mmol) in anisole (2 mL) under nitrogen at -10 °C was treated with trifluoroacetic acid (20 mL) and stirred at 5-10 °C for 2 h The reaction mixture was evaporated / vacuum, and the residue was triturated with a mixture of ethylene ethyl acetate and hexanes (1:1:1). The separated solid was filtered, dissolved in acetonitrile, water mixture and freeze-dried. The crude product obtained was further purified by HP-20 column chromatography using a gradient mixture of dd.H 2 O and acetonitrile (1:0 to 9.4:0.6) to give 3-[2-(2-aminothiazol-4- yl)-(Z)-2-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)imino}-acetamido]-4-fluoromethyl-2-acetidinone-1-sulfonic acid. Yield: 80 mg, 34%; mpt: 200°C decomp.
<1>HNMR (DMSO-de): 8 3,83-4,35 (m, 2H), 4,47-4,63 (m, 1H), 4,68-4,85 (m, 1H), 5,28 (s, 2H), 6,29 (s, 1H), 7,03 (s, 1H), 7,30 (br, s, 3H), 8,12 (s, 1H), 9,45 (d, 1H, <1>HNMR (DMSO-de): δ 3.83-4.35 (m, 2H), 4.47-4.63 (m, 1H), 4.68-4.85 (m, 1H), 5.28 (s, 2H), 6.29 (s, 1H), 7.03 (s, 1H), 7.30 (br, s, 3H), 8.12 (s, 1H), 9.45 (d, 1H,
J=8,1 Hz). J = 8.1 Hz).
Trinn 3: 3-[2-(2-aminotiazol-4-yl)-(Z)-2-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}-acetamido]-4-fluormetyl-2-azetidinon-1-slfonsyre, natriumsalt Step 3: 3-[2-(2-aminothiazol-4-yl)-(Z)-2-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)imino}-acetamido]-4-fluoromethyl- 2-Azetidinone-1-sulfonic acid, sodium salt
NaHC03 (s, 13 mg, 0,155 mmol) ble tilsatt til en suspensjon av 3-[2-(2-aminotiazol-4-yl)-(Z)-2-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}-acetamido]-4-fluormetyl-2-azetidinon-1-sulfonsyre (80 mg, 0,158 mmol) I destillert vann. Blandingen ble omrørt I 5 min og frysetørket for å gi 3-[2-(2-aminotiazol-4-yl)-(Z)-2-{(1,5-dihydroksy-4-pyridon-2-ylmetoksy)imino}-acetamido]-4-fluormetyl-2-azetidinon-1-sulfonsyre, natriumsalt. NaHCO 3 (s, 13 mg, 0.155 mmol) was added to a suspension of 3-[2-(2-aminothiazol-4-yl)-(Z)-2-{(1,5-dihydroxy-4-pyridon-2 -ylmethoxy)imino}-acetamido]-4-fluoromethyl-2-azetidinone-1-sulfonic acid (80 mg, 0.158 mmol) In distilled water. The mixture was stirred for 5 min and lyophilized to give 3-[2-(2-aminothiazol-4-yl)-(Z)-2-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)imino} -acetamido]-4-fluoromethyl-2-azetidinone-1-sulfonic acid, sodium salt.
Utbytte: 75 mg, 89% Yield: 75 mg, 89%
<1>HNMR (DMSO-de): 8 3,83-4,30 (m, 2H), 4,47-4,64 (m, 1H), 4,73-4,84 (m, 1H), 5,13 (s, 2H), 5,30 (s, 1H), 6,55 (s, 1H), 6,74 (s, 1H), 7,27 (br, s, 23H), 7,57 (s, 1H), 9,57 (br, s, 1H). <1>HNMR (DMSO-de): δ 3.83-4.30 (m, 2H), 4.47-4.64 (m, 1H), 4.73-4.84 (m, 1H), 5.13 (s, 2H), 5.30 (s, 1H), 6.55 (s, 1H), 6.74 (s, 1H), 7.27 (br, s, 23H), 7.57 (s, 1H), 9.57 (br, s, 1H).
Test for antibakteriell aktivitet Test for antibacterial activity
Forbindelsene ifølge foreliggende oppfinnelse ble testet for minimum inhibitorisk konsentrasjon (MIC) mot bakteriene oppført i tabell 1 ifølge standard mikrokraft fortynningsmetode som beskrevet i NCCLS dokumentet. Minimum inhibitorisk konsentrasjon blir uttrykt i jag/ml. The compounds according to the present invention were tested for minimum inhibitory concentration (MIC) against the bacteria listed in Table 1 according to the standard micropower dilution method as described in the NCCLS document. The minimum inhibitory concentration is expressed in µg/ml.
Claims (19)
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| US23261700P | 2000-09-14 | 2000-09-14 | |
| PCT/IB2001/002115 WO2002022613A1 (en) | 2000-09-14 | 2001-09-14 | 3-(heteroaryl acetamido)-2-oxo-azetidine-1-sulfonic acids derivatives as antibacterial agents |
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| CA2629570C (en) * | 2005-12-07 | 2012-11-27 | Basilea Pharmaceutica Ag | Useful combinations of monobactam antibiotics with beta-lactamase inhibitors |
| AU2008231854B2 (en) | 2007-03-23 | 2013-03-21 | Basilea Pharmaceutica Ag | Combination medicaments for treating bacterial infections |
| US20110046101A1 (en) * | 2008-03-17 | 2011-02-24 | Dmitrienko Gary I | Bate-lactamase inhibitors |
| JP6266978B2 (en) | 2010-08-10 | 2018-01-24 | レンペックス・ファーマシューティカルズ・インコーポレイテッド | Cyclic boronate derivatives and therapeutic uses thereof |
| US9012491B2 (en) | 2011-08-31 | 2015-04-21 | Rempex Pharmaceuticals, Inc. | Heterocyclic boronic acid ester derivatives and therapeutic uses thereof |
| UY34585A (en) | 2012-01-24 | 2013-09-02 | Aicuris Gmbh & Co Kg | B-LACTAMIC COMPOUNDS REPLACED WITH AMIDINE, ITS PREPARATION AND USE |
| US9156858B2 (en) | 2012-05-23 | 2015-10-13 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| US10561675B2 (en) | 2012-06-06 | 2020-02-18 | Rempex Pharmaceuticals, Inc. | Cyclic boronic acid ester derivatives and therapeutic uses thereof |
| CN102757405B (en) * | 2012-07-25 | 2014-04-16 | 山东理工大学 | Vanilline derivative containing thiadiazole, preparation method and purpose thereof |
| US9241947B2 (en) | 2013-01-04 | 2016-01-26 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| EA201591004A1 (en) | 2013-01-04 | 2016-02-29 | Ремпекс Фармасьютикалз, Инк. | DERIVATIVES OF BORONIC ACID AND THEIR THERAPEUTIC APPLICATION |
| US9101638B2 (en) | 2013-01-04 | 2015-08-11 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| CA2894891A1 (en) | 2013-01-04 | 2014-07-10 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| RS59488B1 (en) | 2014-05-05 | 2019-12-31 | Rempex Pharmaceuticals Inc | Synthesis of boronate salts and uses thereof |
| EP3139930A4 (en) | 2014-05-05 | 2018-01-17 | Rempex Pharmaceuticals, Inc. | Salts and polymorphs of cyclic boronic acid ester derivatives and therapeutic uses thereof |
| MX2016015093A (en) | 2014-05-19 | 2017-03-27 | Rempex Pharmaceuticals Inc | Boronic acid derivatives and therapeutic uses thereof. |
| EA201692301A1 (en) | 2014-07-01 | 2017-06-30 | Ремпекс Фармасьютикалз, Инк. | DERIVATIVES OF BORONIC ACID AND THEIR THERAPEUTIC APPLICATION |
| US10662205B2 (en) | 2014-11-18 | 2020-05-26 | Qpex Biopharma, Inc. | Cyclic boronic acid ester derivatives and therapeutic uses thereof |
| US10364257B2 (en) | 2014-12-19 | 2019-07-30 | Rempex Pharmaceuticals, Inc. | Apparatus and continuous flow process for production of boronic acid derivatives |
| WO2016149393A1 (en) | 2015-03-17 | 2016-09-22 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| BR112018077015B1 (en) | 2016-06-30 | 2022-05-03 | Qpex Biopharma, Inc | Boronic acid derivatives and therapeutic uses thereof |
| CN107641119B (en) * | 2016-07-21 | 2019-11-08 | 中国科学院上海药物研究所 | Monocycle beta-lactam-siderophore conjugates and its preparation method and application |
| MA47110A (en) | 2016-12-21 | 2019-10-30 | Aicuris Gmbh & Co Kg | POLYTHERAPY WITH SS-LACTAM COMPOUNDS SUBSTITUTED BY AMIDINE AND SS-LACTAMASE INHIBITORS FOR INFECTIONS WITH ANTIBIOTIC RESISTANT BACTERIAL STRAINS |
| BR112020007138B1 (en) | 2017-10-11 | 2023-03-21 | Qpex Biopharma, Inc | BORONIC ACID DERIVATIVES, SYNTHESIS METHODS, PHARMACEUTICAL COMPOSITION AND THEIR USE |
| WO2019144969A1 (en) | 2018-01-29 | 2019-08-01 | 南京明德新药研发股份有限公司 | Monocyclic β-lactam compound for treating bacterial infection |
| EP3781576B1 (en) | 2018-04-20 | 2024-06-12 | Qpex Biopharma, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| JP7179185B2 (en) | 2018-12-18 | 2022-11-28 | メッドシャイン ディスカバリー インコーポレイテッド | Use of monocyclic β-lactam compounds in the manufacture of pharmaceuticals |
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| US11040987B2 (en) | 2019-09-11 | 2021-06-22 | Tennor Therapeutics Limited | Penam derivatives for treating bacterial infections |
| WO2021098840A1 (en) | 2019-11-22 | 2021-05-27 | 南京明德新药研发有限公司 | SULFONYLUREA RING SUBSTITUTED MONOCYCLIC β-LACTAM ANTIBIOTICS |
| EP4079305A4 (en) | 2019-12-19 | 2024-01-10 | Shenzhen Optimum Biological Technology Co., Ltd | Application of compound in drug preparation |
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| US5888998A (en) | 1997-04-24 | 1999-03-30 | Synphar Laboratories, Inc. | 2-oxo-1-azetidine sulfonic acid derivatives as potent β-lactamase inhibitors |
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